High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients

Nephrology Dialysis Transplantation, Sep 2009

Background. Fibroblast growth factor (FGF)-23, a novel bone-derived phosphaturic factor involved in mineral metabolism, is increased in chronic kidney disease (CKD); in dialysis patients, it has been linked to increased mortality rates and vascular calcification (VC). The present investigation aimed to study the factors associated with elevated serum FGF-23 levels in patients treated with long haemodialysis (LHD) sessions and to determine whether a relationship exists between serum FGF-23 levels and patient survival. Methods. All patients treated in one haemodialysis centre from September 2006 were included in the study. Standard laboratory values, medical history, cardiovascular events and risk factors, medication and FGF-23 levels [ELISA (C-Term) Immutopics] were recorded. Patients received haemodialysis three times a week, on a 5- to 8-h schedule. Patient data were analysed according to FGF-23 quartiles. The effect of FGF-23 on the 2-year survival rate was assessed using the Cox proportional hazard model, adjusted for confounding variables and according to the serum phosphate tertiles. Results. The study included 219 patients. Serum FGF-23 levels were high: 7060 ± 13 500 RU/mL (median, 2740 RU/mL). In logistical regressions, only calcaemia (P = 0.002), phosphataemia (P = 0.008) and warfarin use (P = 0.04) were associated with the highest FGF-23 quartile. In the subgroup of patients with an estimated VC score, the third and fourth quartiles of the FGF-23 levels were associated with more severe VC. In multivariate linear regressions, only phosphataemia remained significantly correlated with FGF-23 (P = 0.04). The 2-year mortality rate was significantly higher for haemodialysis patients with serum FGF-23 levels in the higher quartile [P = 0.007; hazard ratio, 2.5 (1.3–5)] than in the first quartile, whereas within the phosphataemia tertiles, the lowest serum FGF-23 quartile was associated with lowered mortality. Conclusion. This study demonstrated a high level of circulating FGF-23 in LHD patients, despite infrequent hyperphosphataemia. However, phosphataemia is still the main factor correlating with serum FGF-23. The association of higher serum FGF-23 levels with mortality and VC, regardless of the serum phosphate levels, has thus been confirmed.

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High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients

Guillaume Jean 0 Jean-Claude Terrat 0 Thierry Vanel 0 Jean-Marc Hurot 0 Christie Lorriaux 0 Brice Mayor 0 Charles Chazot 0 0 Centre de Rein Artificiel , Tassin la Demi-lune, France Background. Fibroblast growth factor (FGF)-23, a novel bone-derived phosphaturic factor involved in mineral metabolism, is increased in chronic kidney disease (CKD); in dialysis patients, it has been linked to increased mortality rates and vascular calcification (VC). The present investigation aimed to study the factors associated with elevated serum FGF-23 levels in patients treated with long haemodialysis (LHD) sessions and to determine whether a relationship exists between serum FGF-23 levels and patient survival. Methods. All patients treated in one haemodialysis centre from September 2006 were included in the study. Standard laboratory values, medical history, cardiovascular events and risk factors, medication and FGF-23 levels [ELISA (C-Term) Immutopics] were recorded. Patients received haemodialysis three times a week, on a 5- to 8-h schedule. Patient data were analysed according to FGF-23 quartiles. The effect of FGF-23 on the 2-year survival rate was assessed using the Cox proportional hazard model, adjusted for confounding variables and according to the serum phosphate tertiles. Results. The study included 219 patients. Serum FGF23 levels were high: 7060 13 500 RU/mL (median, 2740 RU/mL). In logistical regressions, only calcaemia (P = 0.002), phosphataemia (P = 0.008) and warfarin use (P = 0.04) were associated with the highest FGF-23 quartile. In the subgroup of patients with an estimated VC score, the third and fourth quartiles of the FGF-23 levels were associated with more severe VC. In multivariate linear regressions, only phosphataemia remained significantly correlated with FGF-23 (P = 0.04). The 2-year mortality rate was significantly higher for haemodialysis patients with serum FGF-23 levels in the higher quartile [P = 0.007; hazard ratio, 2.5 (1.3-5)] than in the first quartile, whereas within the phosphataemia tertiles, the lowest serum FGF-23 quartile was associated with lowered mortality. Conclusion. This study demonstrated a high level of circulating FGF-23 in LHD patients, despite infrequent hyperphosphataemia. However, phosphataemia is still the main factor correlating with serum FGF-23. The association of higher serum FGF-23 levels with mortality and VC, regardless of the serum phosphate levels, has thus been confirmed. Introduction Fibroblast growth factor 23 (FGF-23), a novel hormone produced by osteoblasts, is involved in the regulation of phosphate and the metabolism of vitamin D. FGF23 was first identified as the cause of a rare hypophosphataemic syndrome accompanied by phosphaturia, a low 1,25(OH)2D serum level and osteomalacia [1]. FGF-23 causes renal phosphate wasting by inhibiting the sodium phosphate cotransporter type IIa (NPT2a) in the renal proximal tubule; moreover, it also suppresses the renal expression of CYP27B1, resulting in the impairment of 1,25(OH)2D synthesis [2]. Further, FGF-23 binds to its receptor via Klotho, a protein produced by the kidney [3]. In chronic kidney disease (CKD), FGF-23 levels rise as the glomerular filtration rate (GFR) declines and phosphate accumulates [4], which, in turn, results in increased renal phosphate excretion and reduced dietary phosphate absorption via 1,25(OH)2D inhibition [5]. In haemodialysis (HD) patients, it has been suggested that high levels of serum FGF-23 are associated with the reduced expression of Klotho [6]. Recent studies have established a relationship between dietary phosphate and serum FGF-23 levels [7] and have shown that phosphate binders reduce FGF-23 levels in HD patients [8]. FGF-23 null mice exhibit increased cardiovascular calcification that is associated with hyperphosphataemia and excess 1,25(OH)2D levels and die prematurely [9,10]. The FGF-23-Klotho axis seems to protect against cardiovascular disease and premature ageing, and the compensatory increase in FGF-23 may prevent vascular calcification (VC) and reduce cardiovascular mortality (CVM). In contrast, CKD patientswho have elevated serum FGF-23 levelsexhibit increased levels of CVM and VC [9]. Additionally, we previously reported a correlation between VC and serum FGF-23 levels [11]. Furthermore, a correlation between serum FGF-23 levels and mortality, which was independent of phosphataemia, has been recently reported in HD patients [12]. Long HD (LHD) results in better control of hyperphosphataemia and use of less phosphate binders [13]. The present study aimed to identify the factors associated with serum FGF-23 levels in LHD and their effect on the 2-year survival rate at our HD centre. All HD patients treated in our centre from September 2006 were included in the study and prospectively observed over 2 years. All clinical data were collected, including the standard laboratory values, which were recorded using the mean of the previous 3 months; medical histo (...truncated)


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Guillaume Jean, Jean-Claude Terrat, Thierry Vanel, Jean-Marc Hurot, Christie Lorriaux, Brice Mayor, Charles Chazot. High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients, Nephrology Dialysis Transplantation, 2009, pp. 2792-2796, 24/9, DOI: 10.1093/ndt/gfp191